DESCRIPTION (applicant's abstract): There are considerable individual differences in vulnerability for drug abuse. We are exploring the possibility that variation might reflect the effects of early experience on the development of neural systems that mediate drug-seeking behavior. While the precise role of the mesocorticolimbic dopamine system in drug self-administration is not clear, this system does appear to be critically involved in drug self-administration. We found that maternal separation in early life decreases dopamine transporter levels and increases extracellular dopamine responses to stress in the n. accumbens in the rat. Likewise, these animals show increased stress-induced sensitization to the locomotor effects of amphetamine and increased behavioral responsivity to cocaine. In the studies proposed here we are examining the effects of maternal separation on dopamine as well as excitatory amino acid responses to stress in the prefrontal cortex. Normally, increased dopamine activity in the prefrontal cortex serves to inhibit dopamine release in the n. accumbens. These studies also examine the question of laterality, comparing responses in the left and right regions of the prefrontal cortex. In a second set of studies we are examining the relationship between individual differences in hypothalamic-pituitary-adrenal responses to stress and those observed in the mesocorticolimbic dopamine systems. Adult animals exposed to maternal separation in early life show increased HPA responses to stress that are associated with elevated levels of corticotropin-releasing factor (CRF) mRNA in the paraventricular n. of the hypothalamus and the central n. of the amygdala. Piazza and colleagues have suggested that adrenal glucocorticoids regulate dopamine responses to stress in the n. accumbens as well as behavioral sensitization to repeated stress or psychostimulant drug administration. These studies examine the possibility that the effects of maternal separation on ascending dopamine systems may be mediated, in part, by differences in glucocorticoid and/or CRF activity. Finally, we are examining the potential influence of selected neuropeptide regulators of mesocorticolimbic dopamine systems, such as enkephalin and dynorphin systems. These studies are based on recent findings from the McEwen lab that these neuropeptide systems might mediate individual differences in behavioral responses to stress. We feel that these studies will provide us with an understanding of the way in which early environmental events might contribute to the development of individual differences in neural systems that mediate drug-seeking behavior.